The year Led Zeppelin released its first album, in 1969, doctors in California found that they could sometimes spot Y chromosomes in some cells collected from a pregnant woman’s blood. It meant the cells came from the baby, assuming it was a boy.
The presence of fetal cells circulating in maternal blood immediately suggested that capturing and analyzing them could be a way to test fetuses for genetic abnormalities. But the race to do so turned into 50-year ordeal, and most scientists involved in the effort abandoned it. As it turns out, fetal cells in a pregnant woman’s blood are fairly rare. An ounce of blood might have 10 of them, or sometimes none, and they are hard to find.
One who didn’t give up is Art Beaudet, a widely acclaimed physician-researcher and professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, who says his lab now has preliminary evidence that such a blood test is possible. “The skepticism that anyone will ever get this to work is huge,” acknowledges Beaudet, who estimates that up to a dozen biotech companies founded to develop fetal-cell-based prenatal diagnostics have admitted defeat and shut their doors. “It’s been a long, hard slog.”
The reason such a test could transform prenatal medicine is that one fetal cell typically carries a perfect copy of a fetal genome. If scientists are able to reliably and repeatedly capture such cells in a mother’s blood, it would mean an unprecedented treasure trove of data—and a way to identify fetuses with severe genetic problems before birth. Eventually, if such a test were widely adopted, information on every DNA letter in every baby-to-be could be revealed.
Currently, many women opt for a different kind of blood test that scans for fetal DNA floating in a mother’s bloodstream. These NIPT tests (for “noninvasive prenatal testing”) have been a commercial boon because they are an easy and inexpensive way to screen for Down syndrome, which is caused by an extra chromosome. But Beaudet thinks they’ve unwittingly raised the number of genetic abnormalities going undetected, because while they don’t spot smaller genetic problems, they’ve cut the number of women who seek out traditional amniocentesis—the gold standard of prenatal testing, which involves inserting a long needle into a pregnant woman’s abdomen to collect cells for analysis.
Beaudet says what motivated him is “the constant flow of families giving birth to infants with very severe disabilities.” The test will start out by identifying deletions and duplications within a chromosome (that is, missing or additional portions), including those classified as “de novo,” which means they’re new to the fetus rather than being inherited from the parent. Like NIPT, the cell-based testing would also find larger chromosomal errors such as trisomies, or extra copies of a chromosome.
Once that process is established, Beaudet would move on to finding smaller de novo mutations, which crop up in around 500 genes and affect as many as one in 200 pregnancies. Taken together, these errors are five times as frequent as Down syndrome, he says. They are responsible for a range of rare conditions, including some cases of autism and Prader-Willi syndrome, which results in intellectual disability and uncontrolled hunger that can lead to obesity.
Beaudet has worked with two companies, Arcedi Biotech and RareCyte, which have technology for spotting and picking out one cell from millions in a blood sample. RareCyte, based in Seattle, uses a scanner the size of a large microwave to look at blood samples from pregnant women and spot trophoblasts, or cells from the placenta that share the fetus’s DNA. A microscopic straw is used to suck up a given cell. The Baylor scientist says his data show it’s feasible to analyze DNA from single cells in ways that mimic the results of other tests, but he admits the technology isn’t yet automated or consistent enough to be offered routinely. “We have made phenomenal progress in the last two years,” he says. “But we have to prove over time that we’re going to be different.”
Diana Bianchi, a geneticist and neonatologist at Tufts Medical Center, who worked for years to study fetal cells, thinks the task remains too difficult. What’s more, the way DNA gets read out from one cell—it has to be copied many times first—could introduce errors. “It sounds very seductive, like the old boyfriend is saying, ‘Can we get together again?’” says Bianchi. “But I don’t think anything has really changed in the relationship yet. My sense has been that we need a fundamental leap in technology or biology to coax more fetal cells into circulation.”
Bianchi is instead betting on further development of existing prenatal blood tests. Those tests, which are already widely offered and work well, search for fragments of “cell-free,” or loose, DNA that floats in a pregnant woman’s blood. While more than 90 percent of the DNA belongs to the mother, 5 to 10 percent comes from the placenta or fetus and can be measured using rapid-fire sequencing machines. Such tests can find large problems like an extra chromosome, but because of the way the mother’s and baby’s DNA is mixed together, they can’t yet reliably spot smaller errors that are still serious.
“Art is not a stupid person,” says Ronald Wapner, a clinical geneticist and specialist in maternal-fetal medicine at Columbia University Medical Center, who conducted a similar hunt for fetal cells years ago. “He has been on a crusade to find fetal cells. He’s been working on this a long time. Why the heck go on this crusade? Because it would change everything.”
Eventually, cells could be a way to routinely obtain a complete gene sequence, making it possible to spot even individual changes to DNA letters. With a cell, says Wapner, “you could sequence a fetus and find point mutations [those involving a single nucleotide base], which you can’t practically do now.”
Beaudet hopes that Baylor can scale up to performing 10 tests a week on a research basis within the next few months. The next step would be to market the test, probably for about $3,000, although the price would need to drop to under $1,000 to be competitive with cell-free DNA tests. For the time being, confirmation of results via invasive testing would be recommended.
Beaudet also thinks it’s possible that capturing cells might be a way to sequence the entire genome of a fetus, something he says he will try to do. But the idea that parents could know in advance about their baby’s whole genetic makeup—every health risk or the color of its hair— remains controversial. “There would be some debate about whether it’s fair to the fetus,” says Beaudet. He says Baylor is concentrating instead on spotting devastating health problems: “The important thing is to find very serious mutations that cause very severe disabilities. That’s the focus.”